All vertebrates have developed sophisticated and complex immune systems that provide protection from viral, bacterial, fungal, and parasitic infections. A key feature of the immune system is its ability to specifically discriminate foreign molecules from self molecules. A foreign molecule, or antigen, elicits a cascade of events that constitute the immune response. The immune response coordinates the progressive selection, amplification, and activation of cellular defense mechanisms, ultimately leading to the destruction of the foreign pathogen.
There are two basic classes of immune response: cellular and humoral. The cellular immune response is mediated primarily by T-lymphocytes, or T-cells, which either directly destroy invading microorganisms or stimulate the activity of other immune cells. The cellular immune response is most effective against fungi, parasites, cancer cells, transplanted tissue, and intracellular viral infections. The humoral immune response is mediated primarily by B-lymphocytes, or B-cells, which secrete antibodies into the circulation. The humoral immune response is most effective against bacterial and extracellular viral infections. Antibodies, or immunoglobulins (Ig), bind to molecules on the surface of invading microorganisms which are then inactivated and targeted for destruction by downstream effectors.
The prototypical antibody is a tetramer consisting of two identical heavy polypeptide chains (H-chains) and two identical light polypeptide chains (L-chains) interlinked by disulfide bonds. This arrangement confers the characteristic Y-shape to antibody molecules. Antibodies are classified based on their H-chain composition. The five antibody classes, IgA, IgD, IgE, IgG and IgM, are defined by the .alpha., .delta., .epsilon., .gamma., and .mu. H-chain types, respectively. There are two types of L-chains, .kappa. and .lambda., either of which may associate as a pair with any H-chain pair. IgG, the most common class of antibody found in the circulation, is tetrameric, as described above, while the other classes of antibodies are generally variants or multimers of this basic structure.
H-chains and L-chains each contain an N-terminal variable region and a C-terminal constant region. The sequence of the constant region, which consists of about 110 amino acids in L-chains and about 330 or 440 amino acids in H-chains, is nearly identical among H- or L-chains of a particular class. On the other hand, the sequence of the variable region, which consists of about 110 amino acids, differs among H- or L-chains of a particular class. Within each H- and L-chain variable region are three hypervariable regions of extensive sequence diversity, each consisting of about 5 to 10 amino acids. In the antibody molecule, the H- and L-chain hypervariable regions come together to form the antigen binding site. (Alberts, B. et al. (1994) Molecular Biology of the Cell, Garland Publishing, New York, N.Y., pages 1206-1213 and 1216-1217.)
The immune system is capable of recognizing and responding to any foreign molecule that enters the body. Therefore, the immune system must be armed with a full repertoire of antibodies against all potential antigens. Such antibody diversity is generated by rearrangements of genomic DNA encoding variable and constant regions. In each B-cell, gene segments are joined together by site-specific recombination to form a complete gene encoding an H- or L-chain. Site-specific recombination occurs within highly conserved DNA sequences flanking each gene segment. Because there are hundreds of these segments to choose from, millions of different genes can be generated combinatorially. In addition, imprecise joining of these segments and an unusually high rate of somatic mutation within these segments further contribute to antibody diversification.
An individual B-cell produces identical antibodies that are expressed on the cell surface until the B-cell is stimulated by antigen to secrete these antibodies. Cell surface antibodies are associated with transmembrane proteins involved in signal transduction pathways such as kinase cascades. A candidate for such a transmembrane protein is the mouse immune associated protein 38 (IAP38), whose expression is correlated with immunity to malaria infection. IAP38 is a 38 kilodalton protein with two potential N-glycosylation sites and two putative transmembrane domains. (Krucken, J. et al. (1997) Biochem. Biophys. Res. Comm. 230:167-170.)
Recombinant DNA technology has enabled the production of antibodies engineered for use as therapeutic and diagnostic agents. For example, chimeric proteins and protein compositions comprising the variable regions of antibodies retain antigen-binding specificity but lack H-chain constant regions, which often complicate both in vivo and in vitro downstream applications. (Moore, K. W. and Zaffaroni, A., U.S. Pat. No. 4,642,334.) In addition, rodent antibodies directed against human proteins can be "humanized" by replacing their constant regions with those from human antibodies. (Junghans, R. P. et al. (1990) Cancer Res. 50:1495-1502.) The variable regions of these humanized antibodies recognize human proteins, e.g., disease-associated proteins, while the constant regions activate downstream effectors and prevent the antibodies themselves from being recognized as foreign in a human host. Humanized antibodies have proved to be effective therapeutic agents for the prevention of transplant rejection in primate model systems and for their anti-proliferative activity in breast tumor cell lines. (Brown, P. S. et al. (1991) Proc. Natl. Acad. Sci. USA 88:2663-2667.) In addition, large quantities of humanized antibodies can be produced and purified from bacterial expression systems. (Carter, P. et al. (1992) Biotechnology (NY) 10:163-167.)
T-cells fall into two classes: cytotoxic T-cells, which directly eliminate foreign invaders, and helper T-cells, which stimulate the activity of other immune cells. All T-cells express cell surface receptors that directly bind to antigens. Like antibodies, receptor diversity is generated by "gene shuffling" mechanisms. Unlike antibodies, however, these receptors recognize foreign peptide fragments presented on the surface of an infected cell. For example, a virus-infected cell will degrade viral proteins intracellularly and transport the resulting peptide fragments to the cell surface. The peptide fragments are presented to T-cells in the context of self-identifying proteins called major histocompatibility (MHC) proteins. Cytotoxic T-cells either signal the infected cell to undergo programmed cell death or directly lyse the infected cell. Helper T-cells trigger the activation and proliferation of other immune cells, such as B-cells or macrophages, by secreting signaling molecules such as cytokines. The essential role of helper-T cells in the immune response is demonstrated by the devastating effects of acquired immune deficiency syndrome (AIDS), in which the HIV retrovirus severely depletes the number of helper T-cells.
Rejection of transplanted tissue is mediated by T-cell recognition of foreign MHC molecules. Animal models have helped elucidate the molecular basis for the rejection of allografts, which are tissue transplants between two genetically dissimilar individuals of the same species. Rejection of heart transplants between two different rat strains is characterized by arteriosclerosis associated with blood vessels of the donor heart. Activated macrophages and T-cells from the transplant recipient infiltrate the vessel lumen and attract proliferating smooth muscle cells. This inflammatory response is correlated with increased expression of allograft inflammatory factor-1 (AIF-1) in activated macrophages. AIF-1 expression is stimulated by T-cell-derived cytokines such as IFN-.gamma.. AIF-1 cDNA predicts a 147-amino acid protein of 16.8 kilodaltons. AIF-1 contains a single EF-hand calcium binding domain, although the functional relevance of this motif is unknown. A human AIF-1 homolog with 90% amino acid identity to the rat protein has been identified and may likewise play a key role in macrophage-mediated cardiac rejection. (Utans, U. et al. (1995) J. Clin. Invest. 95:2954-2962; Utans, U. et al. (1996) Transplantation 61:1387-1392.)
The major organs of the immune system are classified as either primary or secondary lymphoid organs. Primary lymphoid organs include the bone marrow, which produces B-cells, and the thymus, which produces T-cells. Upon maturation, B- and T-cells travel through the lymphatic system and populate secondary lymphoid organs throughout the body such as the lymph nodes, adenoids, tonsils, spleen, and intestinal Peyer's patches.
Disorders associated with the immune system, in addition to those discussed above, include various autoimmune diseases caused by failure of the immune system to discriminate self from non-self molecules. In addition, diseases associated with immune cell proliferation include multiple myeloma, in which antibody-secreting tumors develop from bone marrow cells. Immunodeficiency, brought on by a variety of diseases and agents including HIV, renders afflicted individuals susceptible to severe and sometimes fatal bacterial and viral infections. (Golub, E. S. et al. (1987) Immunology: A Synthesis, Sinauer Associates, Sunderland, Mass., pages 481 and 509-530.)
The discovery of new human immune system associated proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of immune and cell proliferative disorders and infections.